Project 1 will focus on the development of lead compounds that target the enoyl-ACP reductase from Plasmodium falciparum. This will be done by developing structure-activity relationships (SAR) for novel series of compounds discovered from high throughput screens (HTS) against the purified recombinant enzyme. The synthesis of structural analogs of hits from the HTS and testing by in vitro enyzme assays will be carried out in collaboration between Sacchettini's lab at Texas A&M University and Dr. Garcia-Bustos's lab at GlaxoSmithKline (GSK). As an integral part of this process, the Sacchettini lab will focus on obtaining the crystal structures of PfENR in complex with the most promising lead compounds. A greater understanding of the detailed interactions between the enzyme and the inhibitor, including specific contacts between functional groups and amino acid side chains, and the conformation of the bound inhibitor, will be derived from the structural analyses and will guide the synthetic chemists. The Garcia-Bustos lab together with other colleagues at GSK will focus on chemical synthesis and medicinal chemistry of the most promising compounds to ensure good pharmacokinetic profiles. GSK will be responsible for a thorough work-up of PK, PD, ADME and toxicity for lead compounds and with their vast experience of developing new pharmaceuticals, this will guarantee the greatest chance of success in the overall aims of the Program Project.